1. Technical Field
The present invention relates to novel proangiogenic compositions, to the method for preparing the same and to the uses, in particular therapeutic uses, thereof for preventing or treating any pathological condition causing ischemic-type complications.
The proangiogenic compositions of the invention open the way to novel cell therapy strategies.
In the description below, the references between square brackets [ ] refer to the list of references given at the end of the text.
2. Related Art
The demonstration of the existence of circulating endothelial progenitor cells (EPCs) and of their potential for use in stimulating angiogenesis and vascular repair is an important advance in the vascular biology field.
These cells can be present in the general circulation either spontaneously in response to various stimuli (pro-inflammatory cytokines, growth factors, ischemia, statins, etc.). These cells, which are involved in vascular repair mechanisms, open up an advantageous therapeutic route for the treatment of ischemic cardiovascular diseases.
Proangiogenic systems of the cell marker/specific ligand type comprising an endothelial progenitor cell comprising the Eph cell marker, in particular EphB4 or EphB1, have been described [1]. In such systems, in order to stimulate angiogenesis, the endothelial progenitor cells comprising the Eph marker are activated by a specific ligand belonging to the ephrin family. Endothelial progenitor cells can be obtained from mononuclear cells originating from the bone marrow, from peripheral blood or from umbilical cord blood. After differentiation, the mononuclear cells of the bone marrow or of the umbilical cord provide a relatively large amount of endothelial progenitor cells which express or comprise the Eph marker. In peripheral blood, there is a very small percentage of mononuclear cells which are circulating EPCs. However, the obtaining of endothelial progenitor cells via several steps (preselection and sorting by cytometry, ex vivo culture, differentiation and maturation of the cells, expansion) requires complex and lengthy manipulations; it is therefore expensive and has a low yield.
It is, moreover, known that the risk factors in cardiovascular diseases can induce vascular and cardiovascular disorders through endothelial dysfunction, said dysfunction possibly leading to a decrease in the number and in the function of the EPCs which are involved in tissue repair [2]. Dysfunction and a lower-than-normal amount of circulating EPCs have been observed in certain individuals with risk factors for cardiovascular diseases such as, for example, hypercholesterolemia, diabetes or hypertension [3].
There is therefore a real need to provide new compositions, which can stimulate angiogenesis at least with the same efficiency as the EPCs of various origins, or even the same intensity as angiogenic factors such as VEGF, and for these new compositions to comprise readily accessible cells not requiring by necessity:                a step of preselection and of sorting by cytometry, of ex vivo culture, of differentiation and/or maturation        or        to be in a mixture with other cells for stimulating angiogenesis.        
There is also a real need to provide new compositions, capable of stimulating the angiogenesis function, comprising cells of which the number remains stable.
There is, in addition, a real need for new proangiogenic compositions, the use of which is easy, reproducible and inexpensive.